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Abstract Background Poorly controlled hypertension (HTN) remains one of the most significant public health problems in the United States, in terms of morbidity, mortality, and economic burden. Despite compelling evidence supporting the beneficial effects of therapeutic lifestyle changes (TLC) for blood pressure (BP) reduction, the effectiveness of these approaches in primary care practices remains untested, especially among African Americans, who share a disproportionately greater burden of HTN-related outcomes. Methods/Design This randomized controlled trial tests the effectiveness of a practice-based comprehensive therapeutic lifestyle intervention, delivered through group-based counseling and motivational interviewing (MINT-TLC) versus Usual Care (UC) in 200 low-income, African Americans with uncontrolled hypertension. MINT-TLC is designed to help patients make appropriate lifestyle changes and develop skills to maintain these changes long-term. Patients in the MINT-TLC group attend 10 weekly group classes focused on healthy lifestyle changes (intensive phase); followed by 3 monthly individual motivational interviewing (MINT) sessions (maintenance phase). The intervention is delivered by trained research personnel with appropriate treatment fidelity procedures. Patients in the UC condition receive a single individual counseling session on healthy lifestyle changes and print versions of the intervention materials. The primary outcome is within-patient change in both systolic and diastolic BP from baseline to 6 months. In addition to BP control at 6 months, other secondary outcomes include changes in the following lifestyle behaviors from baseline to 6 months: a) physical activity, b) weight loss, c) number of daily servings of fruits and vegetables and d) 24-hour urinary sodium excretion. Discussion This vanguard trial will provide information on how to refine MINT-TLC and integrate it into a standard treatment protocol for hypertensive African Americans as a result of the data obtained; thus maximizing the likelihood of its translation into clinical practice. Trial Registration Clinicaltrials.gov NCT01070056

Optogenetics revolutionizes basic research in neuroscience and cell biology and bears potential for medical applications. We develop mutants leading to a unifying concept for the construction of various channelrhodopsins with fast closing kinetics. Due to different absorption maxima these channelrhodopsins allow fast neural photoactivation over the whole range of the visible spectrum. We focus our functional analysis on the fast-switching, red light-activated Chrimson variants, because red light has lower light scattering and marginal phototoxicity in tissues. We show paradigmatically for neurons of the cerebral cortex and the auditory nerve that the fast Chrimson mutants enable neural stimulation with firing frequencies of several hundred Hz. They drive spiking at high rates and temporal fidelity with low thresholds for stimulus intensity and duration. Optical cochlear implants restore auditory nerve activity in deaf mice. This demonstrates that the mutants facilitate neuroscience research and future medical applications such as hearing restoration. [ABSTRACT FROM AUTHOR]

The odorant receptor genes, seven transmembrane receptor genes constituting the vastest mammalian gene multifamily, are expressed monogenically and monoallelicaly in each sensory neuron in the olfactory epithelium. This characteristic, often referred to as the one neuron-one receptor rule, is driven by mostly uncharacterized molecular dynamics, generally named odorant receptor gene choice. Much attention has been paid by the scientific community to the identification of sequences regulating the expression of odorant receptor genes within their loci, where related genes are usually arranged in genomic clusters. A number of studies identified transcription factor binding sites on odorant receptor promoter sequences. Similar binding sites were also found on a number of enhancers that regulate in cis their transcription, but have been proposed to form interchromosomal networks. Odorant receptor gene choice seems to occur via the local removal of strongly repressive epigenetic markings, put in place during the maturation of the sensory neuron on each odorant receptor locus. Here we review the fast-changing state of art for the study of regulatory features for odorant receptor genes. [ABSTRACT FROM AUTHOR]

Mitral and tufted cells (MTCs) of the mammalian olfactory bulb are connected via dendrodendritic synapses with inhibitory interneurons in the external plexiform layer. The range, spatial layout, and temporal properties of inhibitory interactions between MTCs mediated by inhibitory interneurons remain unclear. Therefore, we tested for inhibitory interactions using an optogenetic approach. We optically stimulated MTCs expressing channelrhodopsin-2 in transgenic mice, while recording from individual MTCs in juxtacellular or whole-cell configuration in vivo. We used a spatial noise stimulus for mapping interactions between MTCs belonging to different glomeruli in the dorsal bulb. Analyzing firing responses of MTCs to the stimulus, we did not find robust lateral inhibitory effects that were spatially specific. However, analysis of sub-threshold changes in the membrane potential revealed evidence for inhibitory interactions between MTCs that belong to different glomerular units. These lateral inhibitory effects were shortlived and spatially specific. MTC response maps showed hyperpolarizing effects radially extending over more than five glomerular diameters. The inhibitory maps exhibited non-symmetrical yet distance-dependent characteristics. [ABSTRACT FROM AUTHOR]

Anerve cell receives multiple inputs from upstream neurons byway of its synapses.Neuron processing functions are thus influenced by changes in the biophysical properties of the synapse, such as long-term potentiation (LTP) or depression (LTD). This observation has opened new perspectives on the biophysical basis of learning and memory, but its quantitative impact on the information transmission of a neuron remains partially elucidated. One major obstacle is the high dimensionality of the neuronal input-output space, which makes it unfeasible to perform a thorough computational analysis of a neuron with multiple synaptic inputs. In this work, information theory was employed to characterize the information transmission of a cerebellar granule cell over a region of its excitatory input space following synaptic changes. Granule cells have a small dendritic tree (on average, they receive only four mossy fiber afferents), which greatly bounds the input combinatorial space, reducing the complexity of information-theoretic calculations. Numerical simulations and LTP experiments quantified how changes in neurotransmitter release probability (p) modulated information transmission of a cerebellar granule cell. Numerical simulations showed that p shaped the neurotransmission landscape in unexpected ways. As p increased, the optimality of the information transmission of most stimuli did not increase strictly monotonically; instead it reached a plateau at intermediate p levels. Furthermore, our results showed that the spatiotemporal characteristics of the inputs determine the effect of p on neurotransmission, thus permitting the selection of distinctive preferred stimuli for different p values. These selective mechanisms may have important consequences on the encoding of cerebellar mossy fiber inputs and the plasticity and computation at the next circuit stage, including the parallel fiber-Purkinje cell synapses. [ABSTRACT FROM AUTHOR]

Sensory stimulation conveys spike discharges of variable frequency and duration along the mossy fibres of cerebellum raising the question of whether and how these patterns determine plastic changes at the mossy fibre–granule cell synapse. Although various combinations of high-frequency bursts and membrane depolarization can induce NMDA receptor-dependent long-term depression (LTD) and long-term potentiation (LTP), the effect of different discharge frequencies remained unknown. Here we show that low-frequency mossy fibre stimulation (100 impulses−1 Hz) induces mGlu receptor-dependent LTD. For various burst frequencies, the plasticity–[Ca2+]i relationship was U-shaped resembling the Bienenstok–Cooper–Munro (BCM) learning rule. Moreover, LTD expression was associated with increased paired-pulse ratio, coefficient of variation and failure rate, and with a decrease in release probability, therefore showing changes opposite to those characterizing LTP. The plasticity–[Ca2+]i relationship and the changes in neurotransmitter release measured by varying induction frequencies were indistinguishable from those obtained by varying high-frequency burst duration. These results suggest that different glutamate receptors converge onto a final common mechanism translating the frequency and duration of mossy fibre discharges into a regulation of the LTP/LTD balance, which may play an important role in adapting spatio-temporal signal transformations at the cerebellar input stage. [ABSTRACT FROM AUTHOR]

Variations in intracellular calcium concentration ([Ca2+]i) provide a critical signal for synaptic plasticity. In accordance with Hebb's postulate (Hebb, 1949), an increase in postsynaptic [Ca2+]i can induce bidirectional changes in synaptic strength depending on activation of specific biochemical pathways (Bienenstock et al., 1982; Lisman, 1989; Stanton and Sejnowski, 1989). Despite its strategic location for signal processing, spatiotemporal dynamics of [Ca2+]i changes and their relationship with synaptic plasticity at the cerebellar mossy fiber (mf)-granule cell (GrC) relay were unknown. In this paper, we report the plasticity/[Ca2+]i relationship for GrCs, which are typically activated by mf bursts (Chadderton et al., 2004). Mf bursts caused a remarkable [Ca2+]i increase in GrC dendritic terminals through the activation of NMDA receptors, metabotropic glutamate receptors (probably acting through IP3-sensitive stores), voltage-dependent calcium channels, and Ca2+-induced Ca2+ release. Although [Ca2+]i increased with the duration of mf bursts, long-term depression was found with a small [Ca2+]i increase (bursts <250 ms), and long-term potentiation (LTP) was found with a large [Ca2+]i increase (bursts > 250 ms). LTP and [Ca2+]i saturated for bursts > 500 ms and with theta-burst stimulation. Thus, bursting enabled a Ca2+-dependent bidirectional Bienenstock-Cooper-Munro-like learning mechanism providing the cellular basis for effective learning of burst patterns at the input stage of the cerebellum. [ABSTRACT FROM AUTHOR]